Hematopoietic Stem Cell Transplant in Adults with Sickle Cell Disease: the changing landscape

Transcription

1 Hematopoietic Stem Cell Transplant in Adults with Sickle Cell Disease: the changing landscape Adetola Kassim, M.D. Associate Professor of Medicine Vanderbilt-Meharry-Matthew Walker Center of Excellence for Sickle Cell Disease Vanderbilt University Medical Center Nashville, Tennessee

2 Outline Sickle cell disease morbidity Hematopoietic stem cell transplant in SCD what we have learnt so far The challenges in the adult patient Transplant approach in the adult patient Future directions

3 Case 51 year old AAM, lawyer, with sickle cell disease (SCD), Hb SS, h/o recurrent pain episodes, ACS, depression, DVT, cholecystectomy, chronic fatigue and poor QOL. Treatment in the past included: hydrea ( ), decitabine, thalidomide, on chronic transfusion, presented for transplant consultation Other medical problems: - Transfusional iron overload - Sickle cell nephropathy - AVN of the Left femoral head - Priapism with secondary impotence

4 Outcome of sickle cell anemia: A 4-decade observational study of 1056 patients Childhood survival improved from 79% to 89% 73% had 1 or more clinically recognized forms of irreversible organ damage. By the fifth decade, 48% had documented irreversible organ damage. ESRD 11.6% Sickle cell chronic lung disease 16% (often associated with pulmonary hypertension) Cerebrovascular accident 11% Powars et. al. Medicine. 84(6): , November 2005.

5 Improved survival of sickle cell disease 1.0 Fraction Surviving Follow-Up (Years) Quinn et al. Blood Apr 29;115(17):

6 Age at death for individuals with SCD from CDC compressed mortality reports Hassell, K.L. (2010) AJPM, 38, S512 S521.

7 Factors associated with survival in a contemporary adult SCD cohort OS curves by genotype Survival by pain crises/yr Elmariah et al., Am. J. Hematol., 2014 vol. 89(5) pp

8 Factors associated with survival in a contemporary adult SCD cohort Characteristics Hazard ratio P value Pulmonary hypertension Leg ulcer Proteinuria Cerebrovascular event Stroke Seizure 2.54 < Pain crisis in past year Antihypertensive Short-acting narcotics (daily) svcam Elmariah et al., Am. J. Hematol., 2014 vol. 89(5) pp

9 Factors associated with survival in a contemporary adult SCD cohort OS by organ severity score Other end-points Effect of organ severity score was additive (p < 0.001) Median OS - 61years HbSS and HbSβ 0-58 years HbSC and HbSβ year HU and HbF had no effect on survival Elmariah et al., Am. J. Hematol., 2014 vol. 89(5) pp

10 Let s look at the impact of sickle cell disease on a specific organ, the brain.

11 Direct effects of sickle cell disease Overt stroke on the brain Silent stroke Anemia

12 Overt strokes Most widely recognized cause of brain injury in SCD Occur in 5 10% of children with SCD Highest incidence of first stroke: ages 2 5 Rate of stroke recurrence is around 70% Blood transfusion therapy can decrease recurrence to around 10%

13 Stroke free interval versus sickle cell phenotype

14 Hemorrhagic Stroke Most common in adults Peak incidence between 20 to 29 years of age Subarachnoid hemorrhages most common The hemorrhagic predominance may reflect the development of "moya-moya" syndrome years after an earlier thrombotic stroke Angiography reveals the complex filamentous structure of the moya-moya lesion

15 Secondary prevention of overt strokes Therapies for prevention of second strokes: Chronic blood transfusion therapy Allogeneic stem cell transplant Hydroxyurea Revascularization

16 Summary of treatment of stroke Recurrence Rate 22% (2.2 per 100 pt yrs) with transfusion (J Pediatr. 2002;140(3):348-54) 50% with cessation of transfusions (J Pediatr 1991; 118(3): ) 67 % without treatment (Am J Med. 1978;65(3):461-71) *Risk higher in first 2 yrs after initial stroke Initial treatment should include exchange transfusion (J Pediatr. 2006,149(5):710-2) Approximately 45% of the patients that are rigorously transfused will have progressive disease (overt or silent strokes) Blood Jan 20;117(3):772-9 Progressive CNS lesions based on progressive vasculopathy

17 Event-free interval of new overt or silent cerebral infarcts in children with SCD while on transfusion therapy for secondary stroke prevention. 11/40 with new SCI 7/40 new over strokes 45% with progressive cerebral infarcts, mean follow-up of 5.2 years Hulbert et al, 2011

18 Given the rate of cerebral infarcts in children (37% before 18 years of age), coupled with the high rate of cerebral hemorrhage in adults, we elected to introduce as standard of care MRI and MRA imaging evaluation in adults

19 Rationale High pre-test probability > 37% Detection of either silent cerebral infarcts or moya moya would significantly alter medical care Cognitive testing Alter expectations Consideration for blood transfusion therapy or Hematopoietic stem cell transplant (HSCT) Ongoing CNS imaging surveillance

20 Preliminary findings of MRI/MRA result in adult patients with SCD Implemented as standard of care in 2011 n=69 ( predominantly HbSS -57) 9% with aneurysms ( ~ 5% in general population); 6 patients with moya moya 6 patients were recommended to have a neurological procedure 2 agreed to the neurosurgical procedure

21 Consequence of stroke in SCD High recurrence rate (progressive) Motor, speech, sensory impairment Cognitive impairment Excessive iron stores secondary to transfusions Burden of chelation due to transfusion therapy Death

22 Neurocognitive functioning in a clinical sample of adult patients with sickle cell disease (n = 41)

23 Clinical Cognitive Assessment Program 2.5-hour battery of tests and questionnaires that measures: ~ General Intelligence (IQ) ~ Memory ~ Executive Function ~ Psychosocial Adjustment Goal: to identify signs of impairment and assist medical team in developing plan of care

24 Patient scores on cognitive tests compared to population mean Domain/Test Patient Mean (SD) Population Mean (SD) p value IQ (Wechsler Adult Intelligence Scale-IV) Full Scale IQ 85.5 (13.9) 100 (15) <.001 Verbal Comprehension Index 89.2 (13.5) 100 (15) <.001 Perceptual Reasoning Index 89.8 (15.8) 100 (15) <.001 Working Memory Index 86.6 (11.7) 100 (15) <.001 Processing Speed Index 85.1 ( 13.7) 100 (15) <.001

25 Cognitive test scores in patients with overt strokes vs no overt strokes Test Overt Stroke No Overt Stroke p value Full Scale IQ 83.7 (22.9) 85.8 (11.9) Not Significant Total Memory Recall 30.1 (8.8) 40.5 (11.1).026 Executive Functioning 5.3 (3.7) 7.7 (2.5).033

26 Relation between cognitive functioning and employment status Test Employed/In School Unemployed p value Full Scale IQ 93.1 (12.6) 78.9 (11.6).001 Total Memory Recall 41.1 (11.8) 36.8 (10.9) Not Significant Delayed Memory Recall 43.9 (13.3) 35.5 (12.0).04 Executive Functioning 8.1 (2.5) 6.7 (3.0) Not Significant

27 Given the high rate of CNS morbidity, and progressive organ dysfunction, can we abate progression of the disease?

28 Outcome after transplantation for 50 children with advanced, symptomatic SCD An event is defined as death, graft rejection or recurrence of sickle cell disease Walters et al. Blood 2000; 95:6

29 Late effects evaluation 55 long-term survivors >2yrs post-bmt Median age 9.4 year (range ) No patient had an additional stroke or SCI All patients had abrogation of SCD related clinical symptoms such as pain and ACS Significant gonadal toxicity >females Unchanged or improved pulmonary function Walters et al. BBMT 16: (2010)

30 Outcome of patients with hemoglobinopathies given either cord blood or BMT from an HLA-identical sibling: Eurocord-EBMT Overall survival Other outcomes Median age 6yrs and 8yrs Median year 2001 vs 1999 for CBT v BMT respectively Median follow-up 70 months DFS did not differ in both GVHD: BMT > CBT Graft failure: CBT > BMT Outcomes were comparable Franco Locatelli, et al. Blood, 2013

31 Long-term outcome and evaluation of organ function in Pediatric patients with SCD following HSCT- St. Judes experience Matched related donor (n=14) Haploidentical (n=8) Dallas et. al Biol Blood Marrow Transplant 19 (2013)

32 Late effects: MRD or Haplo Indication: stroke, recurrent ACS and VOE Median follow-up: yrs / yrs Greater risk of GVHD in both arms Higher risk of graft rejection in Haplo arm Beneficial outcomes similar in both arms - No recurrent stroke or SCI, MRI improved - Stable NCT with no change in IQ post-hsct - Decline in DLCO, renal and cardiac function in MRD cohort, likely due to conditioning Dallas et. al Biol Blood Marrow Transplant 19 (2013)

33 Health related quality of life in children with SCD and thalassemia following HSCT Kelly et al. Pediatr Blood Cancer October ; 59(4):

34 Benefits Benefits and risks of HSCT Curative in SCD Halts and reverses chronic end-organ damage Improved overall QOL Risks Early and Late regimen related toxicities Increased risk of infertility Growth disturbance in children 5% long term increased risk of secondary cancer

35 Hematopoietic stem cell transplant (HSCT) for SCD by donor type and Transplantation for SCD Total Type of donor HLA identical CB related and unrelated Haploidentical donor Other unrelated donor overall survival EBMT-Eurocord ( ) CIBMTR ( ) Overall survival 1 year 2 year 95% + 1% 94% + 1% 96% + 2% 94% + 1% Eliane Gluckman, ASH 2013

36 The challenges Severely shortened life span in adults with SCD (mean age of death 38.2 years , unchanged from the early 90s) Improved survival into adulthood has uncovered true natural history of adult SCD with progressive organ damage with significant morbidity and mortality Goal: sustained donor engraftment with minimal toxicity using novel approaches

37 Other concerns Need to avoid the high morbidity and mortality associated with conventional bone marrow transplantation (BMT) What level of hematopoietic chimerism alleviates both disease related morbidity, and prevents silent organ damage The scarcity of acceptable stem cell donors No hard & fast indications for transplant

38 Approach to HSCT in the adult patient.. Primum non nocere (first do no harm)

39 Summary of earlier non-myeloablative transplant experience 2000 Van Besien 2002 Van Besien 2003 Iannone 2002 Schleuning 2008 Krishnamurti Number Conditioning Flu, Mel, ATG Flu, Mel, campath Flu, 200 TBI, ATG Immunosupp Tacro, MTX Tacro or CSA, MMF Flu, Cy CSA, MMF Flu, Bu, ATG, TLI CSA Age 40, 56 19, 24 3 to to 18 Engraftment Rejection Acute GvHD (Gr 2) 0 1 (Gr 2) Chronic GvHD (limited) Mixed chimerism Death 2 (GvHD) total

40 In the adult patient with an HLA identical sibling

41 NIH protocol 03-H-0170 non-myeloablative stem cell transplant Alemtuzumab (1 mg/kg total) TBI 300 cgy Unmanipulated G-CSF mobilized PBSC infusion Sirolimus (target ng/dl) Hydroxyurea is continued through day -8 Red cell exchange to lower HbS ~ 30% Platelet transfusion threshold is 50k/uL (to prevent CNS bleeding) Taper immunosuppression planned at 1 year post transplant, if CD3 donor chimerism is >50% Hsieh et al. N Engl J Med 2009;361:

42 Update on protocol 03-H-0170 Overall survival, 100% 30 SCD patients transplanted Disease free survival, 87% 22 patients with white cell engraftment 3 patients with rejection Survival 21 patients with donor red cell engraftment 1 patient with delayed red cell engraftment (antidonor RBC antibody) No GvHD -Median f/up >3 yrs -Age 17-65yrs -GCSF primed PBSC -Graft failure 3/26

43 How about the adult SCD patient without an HLA identical sibling?

44 Haplo-identical Transplant for Sickle Cell Disease and other Hemoglobinopathies

45 Proof of principle Non-myeloablative regimen, suggests that the procedure can be performed in patients who are ineligible for myeloablative allobmt Expands the donor pool for eligible patients Immune suppression approach reduces risk of graft rejection and minimizes GVHD

46 Mechanism of tolerance induction by high dose cytoxan Leo Luznik, Paul O Donnell and Ephraim Fuchs, Semin Oncol. 2012

47 Conditioning schema -First 2 pts were transplanted w/o ATG -Sirolimus replaced tacrolimus w/ 11 pt to reduce the incidence of PRES 2012 by American Society of Hematology Bolaños-Meade J et al. Blood 2012;120:

48 Outcomes data 19 patients screened, 17/19 were transplanted (89%) 14 -haploidentical; 3 -HLA-matched related donors. Eleven patients engrafted durably. After median follow-up of 711 days (minimal follow up 224 days), 10 patients are asymptomatic, and 6 patients are off immunosupression. Only 1 patient developed skin-only acute GVHD that resolved without any therapy. No mortality Bolaños-Meade J et al. Blood 2012;120:

49 Limitations No assessment of whether there was attenuation of end organ disease, specifically CNS, lung or kidneys Graft failure, 43% in haploidentical pairs, remains a major obstacle

50 Pros and cons of three existing of allobmt approaches in patients with SCD Myeloablative matched allobmt Non-myeloablative matched allobmt Pros Curative Does not exclude SCD patients with end-organ damage Large experience Good rates of engraftment May attenuate end-organ damage EFS 85%; OS 97% More available to adults with SCD (30%) TRM < 5% EFS 79%; OS 95% Non-myeloablative mismatched (haplo) allobmt Does not exclude SCD patients with end-organ damage Available to most SCD patients (>50%) TRM < 5% EFS 58%; OS 96% Cons Limited availability ~10% Limited experience Limited experience Limited to children less than 16 yrs old Graft rejection (11 50%) Graft rejection (40-50%) TRM 7% Acute and chronic GVHD No GVHD

51 International Consortium Vanderbilt team o Haydar Frangoul o Michael Debaun o Adetola Kassim Johns Hopkins team o Robert Brodsky o Kenneth Cooke UAB team o Racquel Shelton UK Team o Josu de la Fuente o Baba Inusa o Paul Telfer French team o Nathalie Dhedin o Francoise Bernaudin o Mariane Demontal o Mathieu Kuentz

52 Update on collaborative effort Created both pediatric and adult transplant consortium for haplo-identical transplant in SCD Common entry criteria and protocol Signed memorandum of understanding To date: 4- patients at VUMC; 3-patients in France JHC - 10/12 (83%, all haplos) engrafted with GCSF mobilized donors; 1 death (TRM 4%) -?IPD; 1-GVHD (4%). Enrollment pending in UAB and UK

53 HSCT approach for the adult patient Adult SCD patient with organ dysfunction (?severity score or CI) HLA identical sibling available No HLA identical sibling Non-myeloablative BM or PBSC* Related non-myeloablative haploidentical BM Other approaches being evaluated: Unrelated cord blood, expanded cord strategies, MUD * Using the haploidentical approach with high dose cytoxan

54 Case: follow-up Patient had no HLA matched sibling Underwent a Haplo-BMT from 58yr old sister Indication: SCD with multiple comorbidities Data D+100: RFLP 100% donor; sorted chimerism CD3 / CD % donor; HPLC: nl hemoglobin Presently: >D +120 from Haplo-BMT Complications: AKI due to sirolimus, and rash (suppurative folliculitis) - resolved

55 I never thought that this could happen in my lifetime. I still have lingering issues from living with SCD for so long; but no NEW organ damage or bone damage will occur to me because I am cured. Special dedication

56 Conclusions Haplo-BMT approach has low toxicity, applicable to adults with severe organ damage Less than full engraftment sufficient to revert the sickle phenotype no acute or chronic GvHD data suggest operational tolerance to donor blood cells Longer follow-up and further accrual to ascertain stable chimerism off immunosuppression reversal of end-organ damage Amended protocol to enroll pediatric patients

57 Acknowledgements Patients and their families Michael Debaun, MD Robert Brodsky, MD Maureen Sanger, PhD Nicoll Hannaway, LCSW Members of the Vanderbilt-Meharry- Matthew Walker Center of Excellence for Sickle Cell Disease